Alzheimer's Disease ("AD") is a dementing disorder characterized by progressive impairments in memory and cognition. It typically occurs in later life; and is associated with a multiplicity of structural, chemical and functional abnormalities involving brain regions concerned with cognition and memory. This form of dementia was first reported by Alois Alzheimer in 1907 when he described a disease of the cerebral cortex in a 51-year-old woman suffering from an inexorably progressive dementing disorder. Although other forms of dementia had been well characterized at the time of Alzheimer's clinical report, his patient was clinically and pathologically unusual, because of her relatively young age and the presence of the then newly described intra-cellular inclusions which have subsequently come to be known as neurofibrillary tangles ("NFTs"). In recognition of this unique combination of clinical and pathological features, the term "Alzheimer's Disease" subsequently came into common usage.
Today, Alzheimer's Disease is considered to be one of the forthcoming scourges of the 21st century. This is due in major part to the aging of the population in concert with data indicating a marked increase in the incidence of dementia with advancing age. Epidemiologic studies suggest that the dementia presently occurs in up to 10% of individuals over the age of 65 and it is estimated that in the United States alone, as many as 4 million individuals may be affected with Alzheimer's Disease. The cost of caring for such individuals is well over 80 billion dollars annually and increasing rapidly.
Since the recognition of this form of dementia as a specific disorder, many different neurobiologic approaches have been undertaken to studying and understanding the nature and the mechanism of action for Alzheimer's Disease, with a view to possible future therapeutic treatments and/or prevention. Representative of the range and diversity of these many neurobiologic approaches are those listed within Table 1 below.
TABLE 1 ______________________________________ Neurobiologic Approaches to the Study of Alzheimer's Disease* Biologic Measures Methods Examples ______________________________________ Brain metabolism In vivo imaging Reduced glucose utili- studies zation in neocortex, esp. parietal and temporal areas Histology of brain Histochemistry, /A4 immunoreactive immunocytochemistry plaques in neocortex and hippocampus Quantitation of Morphometric Reduced number of neurons pathology methods in basal forebrain cholinergic system Neuron size and Golgi Stains Abnormal dendritic shape arborizations Ultrastructure Electron microscopy, PHF in NFT and /A4 fibrils immunocytochemistry in plaques Transmitters and Assays of markers Reduced levels of ChAT, enzymes somatostatin, and CRF in cortex Receptors Binding Assays in Reduced cortical somato- vitro autoradiography statin receptors and in- creased cortical CRF receptors Proteins in abnormal Purification of Decoration of PHF with organelles constituents, analyses antineurofilament and of proteins and other antiau antibodies; tubulin- components, like immunoreactivity in immunocytochemistry GVD; actin in Hirano freeze-fracture/ bodies; /A4 in plaque deep-etch cores and congo philic angiopathy Proteins and their Immunoblots, Phosphorylated 200-kD modifications immunocytochemistry, neurofilament A68 and tau in vitro incorporation associated with NFT; of amino acids aberrant processing APP and PrP amyloid RNAs Hybridization on gels Reduced mRNA in some and in situ; cells; PrP and APP mRNA measurements of present in neurons mRNAs and enzymes acting on RNAs Genes Recombinant DNA Anonymous marker on technology chromosome 21 linked to familial AD; APP gene localized to chromosome 21 ______________________________________ ABBREVIATIONS AD Alzheimer's disease /A4amyloid protein CHAT choline acetyltransferase CRF corticotropinreleasing factor GVD granulovacuolar degeneration kD kilodalton(s) mRNA messenger ribonucleic acid(s) NFT neurofibrillary tangle(s) PHF paired helical filament(s) PrP prion protein *Source: DEMENTIA (Peter J. Whitehouse, Ed.), F. A. Davis Co., Philadelphia, 1993, Chapter 3, pp. 56-57.
In addition, a great many research studies and clinical investigations have been undertaken to study the structural deficiencies, chemical changes, and functional abnormalities both within the brain and within different populations of nerve cells. The depth of such investigations and studies are represented by the following publications: Dementia, (J. Whitehouse, Ed.), F.A. Davis Company, Philadelphia, 1993; Paykel, et al., Arch. Gen. Psychiat., 51:325-332 (1994); Amaducci, et al., Neurology, 36:922-931 (1986); McKhann, et al., Neurology 34:939-944 (1984), Heston et al., Arch. Gen. Psychiatry 38:1085-1090 (1981); Aging of the Brain (Gispen and Traber, editors), Elsevier Science Publishers, Amsterdam, 1983, pages 275-282; Heyman et al., Ann. Neurol 15:335-341 (1984); Brayne C. and P. Calloway, Lancet 1:1265-1267 (1988); Roth et al., Br. J. Psychiatry 149:698-709 (1986); Medical Research Council, Report from the NRC Alzheimer's Disease Workshop, London, England, 1987; Morris et al., Neurology 41:469-478 (1991); Alzheimer's Disease: Senile Dimentia and Related Disorders (Katzman, T. D. and R. L. Bick, editors), Raven Press, New York, 1994, pages 47-51; and the references cited within each of these publications.
In spite of the many research investigations and diverse studies undertaken to date, present clinical evaluations still cannot establish an unequivocal diagnosis of Alzheimer's Disease. To the contrary, the only presently known means for positively proving and demonstrating Alzheimer's Disease in a patient can only be achieved by a brain biopsy or a postmortem examination to assess and determine the presence of neurofibrillary tangles (NFT) and senile (amyloid) plaques in brain tissue. These criteria for the definite diagnosis of Alzheimer's Disease are met only by histologic evidence.
Instead, a set of criteria for the diagnosis of probable Alzheimer's Disease have been described and include: (1) the presence of a dementia syndrome with defects in two or more areas of cognition; (2) progressive worsening of memory and other cognitive function over time; (3) a relatively intact level of consciousness; (4) age at disease onset at a time between 40 and 90 years of age; and (5) the specific absence of any other systemic or central nervous system process that could account for the progressive cognitive deterioration in the individual.
In addition, the probability of an accurate diagnosis in the living patient is augmented by laboratory examinations (such as VDRL and TFT) and by imaging studies (such as computed tomography and magnetic resonance imaging). Such laboratory examinations and/or imaging studies demonstrate the existence and effects of other causes of dementia (such as subdural hematoma, intracranial tumors, infection and brain infarction) and disclose results which are consistent with but are not themselves diagnostic of Alzheimer's Disease. Nevertheless, present clinical diagnoses are wrong in as many as 55% of cases. Thus, there is no sound basis or reliable test methodology at all today for the diagnosis of definite Alzheimer's Disease other than the microscopic examination of histologic evidence from brain biopsy or autopsy material. Instead, the best clinical diagnosis available to date is only a presumptive determination based on criteria which are evaluations of cognitive and neurological functions for that patient.
It is therefore overwhelmingly clear that there has been and remains today a long standing need for an accurate method to diagnose Alzheimer's Disease clinically in a living human subject with substantial certainty and reliability. In addition, were such a diagnostic methodology also able to be non-invasive, rapid in time required for performance, and precise via the accumulation of large quantities of empirical data, such a diagnostic methodology would be recognized by physicians and laymen alike as being a major advance and substantial improvement in this field.
The mydriatic response to eyedrops of the anticholinergic agent tropicamide at very low concentration (0.01%) has been studied in patients with Down's syndrome, with a report that, in comparison with normal subjects, Down's syndrome patients had responses three times greater than normal patients. Sacks, et al., J. Neurology, Neurosurgery, and Psychiatry, 1989:52, 1294-1295. Sacks, et al. state that since patients with Alzheimer's disease appear to show behavioral and cognitive sensitivity to hyoscine, the eyedrop test could be used to distinguish people with Alzheimer's disease from patients with other forms of dementia, allowing for a definitive diagnosis in a living patient. U.S. Pat. No. 5,297,562 states that Alzheimer's disease can be diagnosed before symptoms of dementia occur by determining whether a patient is mosaic for trisomy 21, including by measuring certain characteristics known to be associated with Down's syndrome. Among the characteristics listed by Potter are pupil dilation, with citation to Sacks, et al.
U.S. patent application Ser. No. 08/109,746, filed Aug. 20, 1993, apparently relates to the use of a mydriadic response to diagnose Alzheimer's disease in a patient, including methodologies that use an untreated eye as a control for determining the mydriatic response in a treated eye.